The present invention relates to cisplatin, in general, and in particular to injectable formulations of cisplatin in a unit dosage form.
Cisplatin was first synthesized in 1845 and its cytotoxic properties were reported in 1967 when it was first discovered that cisplatin inhibited cell division. Subsequent animal studies revealed that cisplatin had anti-neoplastic activity. Since cisplatin's introduction into initial clinical trials in the 1970's, it has now grown into one of the most widely used chemotherapy agents for the treatment of various solid tumors. The use of cisplatin for the treatment of tumors is the subject of U.S. Pat. No. 4,177,263.
Cisplatin, since its commercial introduction, has been available only as a lyophilized powder which must be reconstituted with an aqueous solution, such as saline or dextrose, prior to use. However, the aqueous solution necessitates prompt administration in that the shelf life is limited to several hours after preparation. Although the lyophilized product has several advantages, it also suffers from several disadvantages, as well.
The lyophilized product must be reconstituted which by necessity requires some degree of personnel exposure. This is particularly undesirable when the drug is a strong cytotoxic anti-neoplastic agent. This hazardous personnel exposure is aggravated by aerosilization of the potent cytotoxic agent. The dissolution of the lyophilizate necessitates additional entry into the vial with a syringe to add solubilizing agent and with each accession of the vial small quantities become airborne, the result being known as aerosolization. The added exposure requires particular precautions, such as the use of rubber gloves and masks. Furthermore, reconstitution introduces the potential for dilution errors. Because of the foregoing reasons, producers and consumers alike prefer readily injectable liquid formulations of parenterally administered drugs.
Because of the desirability of a liquid formulation of cisplatin, efforts have been made to develop such formulations. In this respect, reference is made to U.S. Pat. Nos. 4,310,515 and 4,451,447. The '515 patent is concerned with certain aqueous solutions of cisplatin, whereas the '447 patent concerns liquid cisplatin formulations in which the solvent comprises polyethylene glycol or methoxypolyethylene glycol, or mixtures thereof, in combination with water. The latter compounds suffer from the disadvantage that they themselves introduce undesirable organic products as part of the administration of the active agent. On the other hand, while the compositions of the '515 patent do not introduce an organic material, upon injection, they do suffer from the disadvantage that they are extremely acidic in nature, with the pH being in the range of 2.0 to 3.0, a pH of 2.5 being preferred.
Of course, for solutions for injection, one consideration is the patient comfort, upon infusion of the product. One of the factors which impacts patient comfort is the pH of the infused solution. Therefore, it is generally recognized that the closer the pH is to that of blood (7.4), the less likelihood of patient discomfort upon infusion. A disadvantage of the compositions of the '515 patent then is that the pH of the formulations is highly acidic, the pH being substantially lower than that of blood. Besides general patient discomfort, such a low pH can cause localized phlebitis at and around the site of injection.
A need has therefore existed for a liquid cisplatin formulation which causes less patient discomfort, upon infusion, and which possesses sufficient stability such that it can be manufactured, stored, and used, without substantial degradation.